Biochemical and Biophysical Research Communications
Calcineurin regulation of neuronal plasticity
Section snippets
Inhibitor-1 and DARPP-32
A powerful mechanism by which CaN mediates diverse cellular effects is through the disinhibition of PP1. A serine/threonine phosphatase of broad specificity, PP1, is targeted to discrete subcellular locales proximal to its substrates throughout the brain [20]. The activity of PP1 is tightly regulated by several proteins including inhibitor-1 (I-1), which is expressed in various brain regions [21], [22], and the dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), which is heavily
Cytoskeletal proteins
A key component of the neuronal cytoskeleton, microtubules are important for neuronal morphology, axonal transport, neurite outgrowth, and connectivity [36], [37], [38]. Microtubules are primarily composed of α- and β-tubulin, and microtubule-associated proteins (MAP) such as MAP2 and tau. The function of microtubules is largely influenced by dephosphorylation. For example, CaN dephosphorylation of tubulin, which is opposed by protein kinase A (PKA) and CaM-dependent protein kinase II (CaMKII),
Enzymes involved in neurotransmitter synthesis
The enzymes neuronal nitric oxide synthase (nNOS) and l-glutamate decarboxylase (GAD) have been identified as substrates for CaN modulation. Localized within post-synaptic terminals, nNOS synthesizes nitric oxide (NO) from l-arginine and molecular oxygen, leading to the activation of guanylyl cyclase (GC) and cGMP production [50], [51], [52]. NO is considered an unconventional neurotransmitter, as it freely diffuses across membranes, affecting GC-mediated signaling in proximal post-synaptic
Calcineurin regulation of activity-dependent gene expression
As described in the previous sections, rapid changes in synaptic strength are mediated by post-translational modifications of preexisting proteins. Enduring changes, however, are also dependent upon the induction of gene expression and protein synthesis [132], [133], [134]. CaN influences multiple transcription factors including MEF-2 [135], [136], [137], [138] and NF-κB [139]. Here we describe two mechanisms by which CaN regulates activity-dependent gene expression: (1) inhibition of CREB and
Summary
CaN exerts a powerful effect on a variety of signaling proteins within neurons. Depending upon the strength, duration, and site of a Ca2+ stimulus, CaN may either increase or decrease synaptic efficacy and cell excitability, through modulation of ion channels, neurotransmitter receptors, cytoskeletal proteins, kinases, other phosphatases, and transcription factors. Thus, in response to multiple forms of synaptic stimulation, CaN initiates both short- and long-term changes on neuronal function,
Acknowledgements
R.D.G. is supported by NIH training Grant DA07234. R.L.D. is supported by a Duke University post-doctoral fellowship. P.G.M. is supported by NIH Grant NS41302 and the Whitehall Foundation. The authors would like to thank Jeremy Bergsman, Karl Deisseroth, Geoffrey Pitt, Mark Thomas, and Ann Isaksen for the critical reading of the manuscript.
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2022, Neuroscience ResearchCitation Excerpt :CNs also increase the ability of tubulin to assemble into microtubules and its affinity to microtubule-associating proteins, such as MAP2 and tau, thus promoting structural stability of neuronal elements (Goto et al., 1985; Yamamoto et al., 1985; Mandelkow et al., 1995). Furthermore, CNs give profound effects upon cellular function, differentiation, plasticity, and survival by regulation of gene expression in response to Ca2+ signals, which is exerted through dephosphorylation of key transcription factors, such as cAMP responsive element binding protein (CREB) and nuclear factor of activated T cells cytoplasmic, CN-dependent 4 (NFATc4) (Growth et al., 2003). The wide distribution of CNA and CNB subunits in various neuron-glial elements should reflect the diversity of CN functions.
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